279 - The exposure-dependent increases in 8-iso-PGF2α and the significance of decoding its sources to identify a specific indicator of oxidative stress or inflammation

Abstract

F2-isoprostanes, 8-iso-PGF2α, have been quantified as biomarkers of oxidative stress in over 1000 distinct experimental and human conditions. However, it has been shown that in addition to the free radical mediated pathway, the inflammation-induced prostaglandin-H-synthase enzymes are a major source of the F2-isoprostane generation. Accounting for the inflammatory source, F2-isoprostanes can be utilized for either a specific biomarker of oxidative stress or a biomarker of inflammation. To distinguish between F2-isoprostanes generated from inflammation vs. oxidative stress, the 8-iso-PGF2α/PGF2α ratio was implemented. With this measure, we have verified that exposure to the classic free radical toxicant carbon tetrachloride in rats predominantly causes an increase in chemical 8-iso-PGF2α (86.6 ± 8.0 % of total at 1200 mg/kg). In contrast, exposure to lipopolysaccharide also induces the formation of F2-isoprostanes; however, the predominant mechanism for this exposure is due to increased enzymatic 8-iso-PGF2α (59.5 ± 7.0 % of total at 0.5 mg/kg). Surprisingly, in human tobacco smokers, we also found that enzymatic lipid peroxidation is the primary source of F2-isoprostanes (Hedges’ g = 0.59 for enzymatic vs. 0.35 for chemical 8-iso-PGF2α). This distribution was independent of sex and age. Another source associated with elevated levels of 8-iso-PGF2α in humans is increased urinary phthalate metabolites and most research has concluded oxidative stress mediated phthalate exposure. In a large population of pregnant women, (N ~ 700), we observed compound dependent associations with lower molecular weight phthalate metabolites being associated with higher levels of chemical 8-iso-PGF2α whereas specific higher, branched chain metabolites are associated with elevated levels of enzymatic 8-iso-PGF2α. Our experimental and human data show the exposure dependent changes in 8-iso-PGF2α and the importance of distinguishing its sources to make it a specific biomarker of oxidative stress or inflammation. Without this additional step of 8-iso-PGF2α / PGF2α ratio determination, data can be greatly misinterpreted.